1. Field of the Invention
The present invention relates to a method for producing .alpha.,.beta.-unsaturated ketolactones which are useful as synthetic intermediates for prostaglandins.
2. Description of the Prior Art
During the study of various kinds of prostaglandin derivatives, it has been found that there exist many prostaglandins having the prostanoic acid skeletone in which has at least one halogen atom, especially fluorine atom, at the 16- or 17- position [16(17)-mono or 16,16 (17,17)-dihalo-prostaglandins] represented by the following formula: ##STR1## that exhibit characteristic pharmacological activities.
Corey method has been well known for a long time and is still a typical synthetic procedure of prostaglandins.
The Corey method includes the step of producing an .alpha.,.beta.-unsaturated ketolactone (III) from Corey lactone via Corey aldehyde (II): ##STR2## [wherein Ar represents an aromatic group.]
Corey lactone (I) is oxidized to Corey aldehyde (II) using the complex of pyridine and chromium trioxide (so called Collins oxidation), followed by a reaction between this aldehyde and an anion generated by reacting a dimethyl (2-oxoalkyl)phosphonate with sodium hydride to give the .alpha.,.beta.-unsaturated ketolactone (III).
These reactions are simply considered to be applicable to the synthesis of 16(17)-mono or 16,16(17,17)-dihalo-prostaglandins. However, when dimethyl (2-oxoalkyl) phosphonates having a or two halogen atoms at the 3-position are used as a replacement of the said phosphonate, the yield of the desired .alpha.,.beta.-unsaturated ketolactone decreases to a level of below 10%.
Many attempts have been made that reactions are carried out under the presence of sodium hydride and a copper compound, or a thallium compound, to improve the yield. Use of the copper compound, however, does not result in an adequate improvement in the yield, while the thallium compound, showing improvement in the yield to some extent as it does, is toxic property and is very expensive. Thus, there has been a desire for further improvement in the reaction step.